Breastfeeding is now widely accepted as important to optimizing health, growth and development of humans and reducing the financial burden for health care in the United States. The current recommendation by the American Academy of Pediatrics is that infants be exclusively breast fed to 6 months of age. Today, most women who choose to breast feed have difficulty maintaining a productive lactation for that long. The most common reason cited for early cessation of breastfeeding is insufficient milk volume. Biological, physiological and even familial factors probably all play a role in determining lactation outcome. To understand this critical variability between women, an understanding of the mechanisms regulating lactation is crucial. In other mammals such as the cow and the mouse milk production is a heritable trait. Despite these findings, however, the genes that contribute to milk production are largely unidentified. In the bovine, there are quantitative trait loci (QTL) for milk volume present on all 29 autosomes. Only a few of the genes underlying these QTL have been identified. In the mouse, even fewer QTL have been published. None of the current mouse QTL studies have published data on milk production during lactogenesis II, milk composition, or mammary gland development, factors that are all important to lactational success in breastfeeding women. Our laboratory uses litter-crossfostering approaches to measure relative milk production in the mouse. These approaches have allowed for indirect measurement of relative milk production capacity during all stages of the cycle with a degree of increased sensitivity and precision that has not been present in previous studies. We have also measured milk composition, mammary gland mitochondrial function and maternal behavior, and conducted extensive analysis of mammary gland development and gene expression over the course of the lactation cycle. These preliminary studies demonstrate that mammary tissue oxidative metabolism is temporally linked to milk production The hypothesis of this proposal is that phenotypic variation in milk production-associated traits among mouse strains will be accounted for by differences in mammary tissue oxidative metabolism and will be linked to QTL identified through in-silico association mapping. Our cross-fostering paradigm will be used to isolate and measure maternal phenotypic differences in important lactation-related traits among a collection of inbred mouse strains known as the mouse diversity panel. We will then determined if these differences are associated with altered mammary mitochondrial function and then conduct In-silico whole genome association scans to identify the QTL linked to these lactation performance and mitochondrial function traits. These QTL will be mapped onto the human Hapmap and serve as the basis for a subsequent RO1 aimed at identifying genes and gene-expression pathways which determine lactation performance in breastfeeding women. PUBLIC HEALTH RELEVANCE: Breastfeeding is now widely accepted as important to optimizing health, growth and development of humans and reducing the financial burden for health care on the United States. The current recommendation by the American Academy of Pediatrics is that infants be exclusively breast fed to 6 months of age. Today, most women who choose to breast feed have difficulty maintaining a productive lactation for that long. The experiments described in this proposal will use powerful new mouse genetic tools to identify and map the genes which could regulate lactation outcomes in breastfeeding women.